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Caspofungin
Indications
Caspofungin acetate is the first antifungal medication of the echinocandins class to receive marketing approval from the Food and Drug Administration (FDA). Caspofungin was introduced in 2001 and approved for use in adults and pediatric patients (3 months and older).[1]
FDA-Approved Indications
- Febrile neutropenia: This condition is defined as a fever over 101 °F (or 38 °C) for 1 hour, with either an absolute neutrophil count (ANC) of less than or equal to 500 cells/μL or, alternately, an ANC of below or equal to 1000 cells/μL with a projected nadir of under or equal to 500 cells/μL. According to the Infectious Diseases Society of America (IDSA), empiric antifungal therapy is recommended for high-risk patients with persistent febrile neutropenia despite broad-spectrum antibiotic therapy. These antifungals include caspofungin, among others.[2]
- Invasive candidiasis: In a double-blind, randomized trial that compared the efficacy of caspofungin with amphotericin B in patients with invasive endocarditis, the more favorable outcome occurred in 73.4% of caspofungin recipients as opposed to 61.7% of amphotericin B recipients.[3] For the initial treatment of candidemia, the echinocandins are preferred agents over azoles under the following conditions: identification or suspicion of either C. glabrata or C. krusei or the patient’s candidemia was refractory to treatment with an azole agent.[4]
- Candida infections: candidemia, intra-abdominal abscesses, peritonitis, and pleural space infections
- Esophageal candidiasis: Several studies have found caspofungin to have a favorable treatment response comparable to fluconazole.[5][6] A year after the introduction of caspofungin in 2002, Villanueva et al conducted a double-blind, randomized trial with 177 HIV patients diagnosed with esophageal candidiasis. Researchers randomly assigned patients to 2 groups: caspofungin (50 mg IV) or fluconazole (200 mg IV), once daily for 7 to 21 days. There was a combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after treatment discontinuation. The treatment response was 81% and 85% for the patients in each group, caspofungin and fluconazole, respectively.[5] The same year, a retrospective analysis performed by Kartsonis et al demonstrated the effectiveness of caspofungin in fluconazole-resistant or refractory esophageal candidiasis. The treatment was successful in 11 of the 14 patients with in-vitro-resistant isolates and 7 of the 11 patients with refractory disease. The use of caspofungin also appears to be associated with less toxic effects than IV amphotericin B in managing esophageal candidiasis.[6][7]
- Invasive aspergillosis: Caspofungin has FDA approval to treat invasive aspergillosis in patients who are refractory to or intolerant of voriconazole, the primary antifungal agent.[1][8][9] Echinocandins are not recommended as first-line therapy.[2]
Off-Label Uses
- Candida spp osteomyelitis or infectious arthritis
- Oropharyngeal candidiasis (thrush)
- Candida spp cardiovascular system infections such as endocarditis and suppurative thrombophlebitis
- Candidiasis prophylaxis and aspergillosis prophylaxis in high-risk patients
Mechanism of Action
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Mechanism of Action
Caspofungin, along with other echinocandins, works by noncompetitive inhibition of the enzyme β-(1,3)-D-glucan synthase, a critical component in the synthesis of the fungal cell wall; this enzyme is not present in mammalian cells.[10]
Caspofungin exhibits fungicidal activity against Candida species, including triazole-resistant isolates, and fungistatic activity against Aspergillus species.[1][10] Caspofungin displays triphasic nonlinear pharmacokinetics. After an initial intravenous administration of the drug, there is a rapid decrease in plasma concentrations due to tissue distribution. This is followed by a gradual re-release of the drug from the extravascular tissues and slow hepatic metabolism.[11][12] The drug undergoes hepatic metabolism via hydrolysis and slow N-acetylation into 2 inactive metabolites; dose reduction is advisable in severe hepatic insufficiency.[11][12][13] Caspofungin also undergoes spontaneous disintegration to an open-ring compound.
The pharmacokinetics of caspofungin also show an increased accumulation as the dose increases, and there is a dose-related dependency in the time to reach a steady state upon multiple-dose administration. Therefore, a loading dose followed by a lower once-daily dose is required to attain an initial therapeutic plasma concentration and avoid drug accumulation. This approach results in a trough concentration of at least 1 μg/mL (proposed target concentration in invasive infections derived from in vitro susceptibility testing of Candida spp).[13][14]
Pharmacokinetics
Absorption:
Caspofungin has negligible oral bioavailability (less than 0.2%) but has 92% tissue distribution within 36 to 48 hours after intravenous infusion.[15]
Distribution:
The drug is well distributed to tissues when administered intravenously, but it exhibits a high level of protein binding (97%).
Metabolism:
Caspofungin is hepatically metabolized via chemical degradation by peptide hydrolysis and N-acetylation, with some CYP450 metabolism. Caspofungin has a short α-phase half-life (t1/2) of 1 to 2 hours (volume of distribution of 9.7 L) and a β-phase t1/2 of 9 to 11 hours that exhibits log linearity. Unlike the other phases, the γ-phase t1/2 of 40 to 50 hours appears nonlinear and responsible for caspofungin accumulation over time. Caspofungin is slowly eliminated from plasma, with a 10 to 12 mL/min clearance.[6][13]
Elimination:
Approximately 75% of a radioactive dose is recovered after 27 days, with 41% in urine and 35% in feces. Only about 2% of caspofungin is excreted unchanged in the urine.[6][13]
Administration
Dosage Forms
Caspofungin acetate is administered solely by the intravenous (IV) route. Because the echinocandins have a large molecular weight, they are poorly bioavailable for oral use. The IV infusion should take place slowly over an hour and not be administered by IV bolus or mixed or co-infused with other medications. Do not use diluents containing dextrose (alpha-D-glucose).
The available doses include 50 and 70 mg per vial powder for injection containers.[12] The dosage varies by patient population.
Adult Dosing
For all indications, administer an initial dose of 70 mg (loading dose) followed by 50 mg once IV daily. The daily dose may be increased to 70 mg if there is no response or if CYP3A4 inducers such as rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin are coadministered. The maximum daily dose should not exceed 70 mg.
For esophageal candidiasis, the dose is 50 mg once daily with no loading dose.
Special Population
Hepatic impairment: The dosage for adult patients with moderate hepatic impairment is reduced to 35 mg once daily, with a 70 mg loading dose on day 1 where appropriate. Dose reduction for patients with hepatic insufficiency is recommended based on the Child-Pugh (C-P) score. However, in critically ill patients, the dose should not be reduced unless there is evidence of liver cirrhosis.[16]
Renal impairment: No dose reduction is necessary for renal impairment; echinocandin passage through the membranes seems low because of high protein binding, 97% to albumin.[17]
Pregnant patients: Clinicians should weigh the risks vs benefits in pregnant patients. No human data is available on this topic. Animal data indicates possible embryo-fetal toxicity.
Breastfeeding patients: Patients may use the drug while breastfeeding; infant harm is not expected based on drug properties. There is no human data regarding caspofungin's effect on milk production.
Pediatric patients: The basis for dosing is on the patient's body surface area. For all indications, a single 70 mg/m2 loading dose on day 1 will be followed by 50 mg/m2 once daily.
Older patients: Trials performed to date have not revealed any data that would limit the use of caspofungin injection in older patients.
Adverse Effects
Caspofungin has a relatively low incidence of adverse effects; the most commonly reported include chills, fever, phlebitis/thrombophlebitis, tachycardia, nausea, vomiting, rash, abdominal pain, headache, and diarrhea.[6] Caspofungin can also increase AST and ALT levels.
Caspofungin has been found to cause skin erosions similar to those seen in toxic epidermal necrolysis (TEN). A case report by Lee et al describes the development of a rash (erythematous macules and plaques) that quickly progressed to blisters and skin erosions after administering caspofungin in an 86-year-old man with disseminated Candida krusei infection.[18] Other rare but potentially severe reactions include Stevens-Johnson syndrome, septic shock, and erythema multiforme.
Drug Interactions
An increase in the maintenance dose of caspofungin is recommended with the coadministration of potent inducers of hepatic CYP3A4 enzymes. These agents include rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin.[6] Using caspofungin with CYP3A4 inducers, the daily dose may be increased to 70 mg. However, the maximum daily dose should not exceed 70 mg.
Concomitant use of caspofungin with cyclosporine has also been linked to increased caspofungin-induced hepatotoxicity. However, several case reports describe patients treated with both drugs without clinically important signs or symptoms of liver toxicity.[19][20][21][22] Combined therapy with cyclosporin should be avoided as this combination could increase caspofungin levels and impact liver enzymes, increasing AST and ALT levels.
Contraindications
The main contraindication to caspofungin therapy is a known hypersensitivity reaction to the formulation's caspofungin acetate or other ingredients. Caution is advised in patients with Child-Pugh Class C hepatic impairment.
There is inadequate data regarding the use of caspofungin in pregnancy; clinicians should use the drug cautiously in this patient population. When treatment of systemic fungal infections is necessary during pregnancy, Amphotericin B is the first-line therapy.[23]
Monitoring
Given caspofungin's potential hepatic adverse effects, monitoring liver function is essential. Caspofungin is known to release histamine in peripheral blood cells, which predisposes patients to potentially developing histamine-mediated symptoms ranging from severe to fatal anaphylaxis. As a result, monitoring patients for anaphylaxis, rash, or histamine-related reactions (eg, facial swelling, bronchospasm, a sensation of warmth) is paramount to decreasing the risk of morbidity and mortality.[24][25][26]
Toxicity
Hepatitis, hepatomegaly, and hyperbilirubinemia can rarely occur. There are also reports of hepatic failure with the echinocandins. Therefore, checking hepatic aminotransferases regularly during caspofungin therapy is recommended.[27]
Enhancing Healthcare Team Outcomes
Caspofungin has significant therapeutic effects, evidenced by its safety profile and minimal drug interactions, but its use still requires the efforts of an engaged interprofessional healthcare team. These factors have led to its use in treating several medical conditions.[1][8] However, it is essential to note the potential adverse effects of caspofungin despite their low incidence.[18] Monitoring patients’ liver function to minimize toxicity is also critical, given this organ metabolizes the drug. Furthermore, caspofungin is associated with some drug-drug interactions, especially CYP3A4 inducers, which cause caspofungin concentrations to become subtherapeutic.[6] Before prescribing caspofungin for patients who are taking several medications, the prescriber/ordering clinician should consult with the following team members:
- The clinical pharmacist ensures that concomitant administration of the patient’s medications and caspofungin is permissible. In drug-drug interactions, the clinical pharmacist should notify the prescribing physician, who can decide the appropriate course of action based on the patient’s clinical findings and comorbidities.
- The obstetrician-gynecologist should provide input on the case for pregnant patients since the use of caspofungin in pregnancy is currently not recommended in the United States.[23] The drug should only be administered to pregnant women if the potential benefit outweighs the potential risk to the fetus.[6]
Nursing staff will also play a significant role in inpatient administration, monitoring treatment effectiveness, checking for adverse effects of the medication, and reporting findings to the healthcare team.
Ultimately, adopting an interprofessional team approach with collaboration with infectious disease physicians and other sub-specialties, primary care physicians, nurses, pharmacists, and other healthcare personnel is essential to facilitate the administration of the drugs based on current guidelines and maximize patient outcomes while minimizing adverse reactions.
References
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Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Aug 15:63(4):e1-e60. doi: 10.1093/cid/ciw326. Epub 2016 Jun 29 [PubMed PMID: 27365388]
Level 1 (high-level) evidenceMora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J, Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. The New England journal of medicine. 2002 Dec 19:347(25):2020-9 [PubMed PMID: 12490683]
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Level 3 (low-level) evidenceKartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. Journal of acquired immune deficiency syndromes (1999). 2002 Oct 1:31(2):183-7 [PubMed PMID: 12394797]
Level 2 (mid-level) evidenceMorris MI, Villmann M. Echinocandins in the management of invasive fungal infections, Part 2. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2006 Oct 1:63(19):1813-20 [PubMed PMID: 16990627]
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Level 1 (high-level) evidence